Transcript Genomic Medicine Institute

Genetics and Genomics Research to
Enable the Practice of Personalized
Cancer Care
Charis Eng, MD, PhD, FACP
Chair, Genomic Medicine Institute
Director, Center for Personalized Genetic Healthcare
Medical Director, Clinical Cancer Genetics Service
Member, Taussig Cancer Institute
Cleveland Clinic
AFMR Transl Med Symposium, April 11, 2011
Contributors to Premature Mortality
Behavior
Genetics
Social
Medical Access Environmental
D.M. Cosgrove, MD, State of the Clinic 2008
April, 2009
Genomic Medicine Institute
Health & Medicine Transformation
Need to Transform Health & Medicine
in the 21st Century
20th Century Medicine
21st Century Medicine
Treat disease when symptoms appear and
normal function is lost
Intervene before symptoms appear and
preserve normal function for as long as
possible
Did not understand the molecular and
cellular events that lead to disease
Understanding preclinical molecular events
and ability to detect patients at risk
Expensive in financial and disability costs
Order of magnitude more effective
Elias A. Zerhouni, M.D
September 13, 2006
Need to Transform Health and Medicine in the 21stCentury
Genomic Medicine Institute
Historical Imperative for Prevention
•Superior doctors prevent the disease.
•Mediocre doctors treat the disease before evident.
Inferior doctors treat the full blown disease.
Nai-Ching (2600 B.C. 1st Chinese Medical Text)
Genomic Medicine Institute
Top Nine Health Industry Issues in 2010
PricewaterhouseCooper’s Health Research Institute
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Medicare and the Drug Plan
Care and Coverage of the Uninsured
Rise of the Healthcare Consumer
Focus on Prevention
Calls for Patient Safety to Drive HealthCare IT Investments
Diminishing Drug Pipeline
Pay for Performance
Technology Backbone
Labor Shortages
Genomic Medicine Institute
Breath of Personalized Healthcare
(ie, Everyone Can Contribute)
• Phenomics
– Meticulous Documentation of Clinical Features
– Objective Means (Not Self Reports)
• Disease Risk Assessment
• Interpretation
– (Must Have Clinical Context[Outcome] and Scientific Content [Research Data])
– To Fellow Professionals
– To Patients / Consumers
• Personalized Risk Management
– Broadest Sense
– Prevention
– Treatment
– Behavior Modification
– And so on
• Ethical, Legal, Social Issues and Education
Genomic Medicine Institute
Breath of Translational Research
• Myth: Translational Research = Drug Development
and Therapeutic Trials
– Caution: This is how NIH defines it!
• Truth: Translational Research = All Patient-Oriented
Research that Spans the Breath to Refine Diagnostics
and Risk Assessment to Genetic Counseling to
Preventative Maneuvers and Therapeutics
• “Right Diagnosis – Right Treatment”
Genomic Medicine Institute
Genetics and Genomics Important Bases for
Personalizing Clinical Care
Genomics
Common
Diseases
(multi-gene, small
effect each)
Eg. Obesity
Heart disease
Diabetes
Autism
Alzhemier’s
THE BIG RED DOG.
A BIG RED DOG.
3,993 number of genes currently known to be associated with disease
out of an estimated 35,000 (~12%)
THE BIG RED DOG.
THE IGR EDD OG.
Genetics
Uncommon,
Mendelian, SingleGene Disorders
(Strong Effect)
Eg. Cystic fibrosis
Lynch syndrome
Hemophilia A
Sickle-cell anemia
Genomic Medicine Institute
Nirvana of Integrated –omics-based
Personalized Healthcare for Cancer
Prioritization & Testing of
Known High Penetrance
Cancer Genes in Setting of
Genetic Counseling
Multiple Generation Pedigree
For Cancer Genetic Risk Assessment
Multidisciplinary Cancer
Consult Including
Genomic Medicine
And Genetic Counseling
Germline Variant Profiling
Clinical Screening,
Preventive Measures,
Behavior Modification
Select Multi-Agent Targeted
Therapy With >99%
Likelihood of Durable
Response & <1% Likelihood
Of Adverse Effects
Biopsy of Cancer
Histopathology
Somatic Genomic Profiling of
Cancer Epithelium & Stroma
Genomic Medicine Institute
Genomic Medicine Institute Mission (Founded Sept, 2005): Genetics and
Genomic Medicine are the Bases for Personalized Healthcare
• To be the expert base for the principles and practice of
genomic medicine
• Scholarly activity (research), academic clinical practice
and education
• Ultimately directed at personalized genetics and
genomics-based healthcare
Genomic Medicine Institute
Eng Program in Context of Genomic Medicine
Institute (GMI) Research and of Cleveland
Clinic
GMI Focus
Bedside
Bench
Eng Lab
Very Basic
Science Research
Already Strong at
Lerner Research Institute
Clinical
Activities
Clinical Cancer Genetics
Very Clinical
Research
Genomic Medicine Institute
• Strengths
Sept, 2005 Situational SWOT
– Strong Basic Sciences (Ripe for Translation) & Infrastructure
– Strong Clinicians and Clinical Materials
• Weaknesses
– Strong Basic Sciences (Lack of Understanding of Translational and Clinical
–
–
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Genetics and Genomics Investigation and Investigators)
Strong Clinicians (Clueless what Translational Research is; Revenue-Driven)
No Clinical Genetics Infrastructure
No Translational Genetics Research Infrastructure
• Opportunities
– Build a “Perfect” Translational Genetics Research Infrastructure
– Initiate Translational Research Multidisciplinary Programs
– Create Comprehensive Clinical Genetics Program
• Threats
– Sisiphus Syndrome
– Scientists and Clinicians Fear Change
Genomic Medicine Institute
Nirvana of Integrated Genetics and Omics-Based
Personalized Healthcare: 2011 & Beyond
Prioritization & Testing of
Known High Penetrance
Cancer Genes in Setting of
Genetic Counseling
Multiple Generation Pedigree
For Cancer Genetic Risk Assessment
Multidisciplinary Cancer
Consult Including
Genomic Medicine
And Genetic Counseling
Germline Variant Profiling
Clinical Screening,
Preventive Measures,
Behavior Modification
Select Multi-Agent Targeted
Therapy With >99%
Likelihood of Durable
Response & <1% Likelihood
Of Adverse Effects
Biopsy of Cancer
Histopathology
Somatic Molecular Profiling of
Cancer Epithelium & Stroma
Genomic Medicine Institute
GMI Faculty Research Programs
Prioritization & Testing of
Genetic Susceptibility to:
Phenotyping by Clinicians
Known(Zhang)
High Penetrance
Eng
Hemostasis and Thrombosis
Genes in Setting of
Moran
Cancer (Eng)
Genetic Counseling
Natowicz
Connective Tissue Disorders (Aldred/Moran)
Shapiro
Multiple Generation Pedigree
Pulm HTN & Wilms Tumor (Aldred)
Zurcher
Clinical Screening,
For Cancer Genetic Risk Assessment
11 Genetic Counselors
Preventive Measures,
Behavior Modification
Genomic Predisposition to Common Diseases:
Diabetes/Obesity (Serre)
Select Multi-Agent Targeted
Therapy With >99%
for
Genomic
Bioethics)
Reverse
Cholesterol
Transport (Sehayek)
Likelihood of Durable
DTC Genomic Testing
(Eng,
Sharp)
Germline
Genome
Malaria
andProfiling
Populations (Serre)
Response & <1% Likelihood
Returning Results to Participants
who Donated
Research
Solid Tumors
(Eng) to Biorepository-Based
Of Adverse
Effects
Genetic Testing in Pediatric Populations
(Moran,
Sharp)
Somatic Genetics/Epigenetics:
Biopsy
of
Tissue
Informed Consent in MFM (Moran,
Farrell) (Eng, Sehayek, Serre)
Metabiomics
Colon CA and Prostate CA Epigenomics (Ting)
Microenvironment
and Outcome (Eng)
Somatic Molecular Profiling of
Wilms Tumor/HNSCC
(Aldred)
Epithelium & Microenvironment
Histopathology
Multidisciplinary
Consult Including
Genomic Medicine
And
Genetic Counseling
Genomics
ELSI (Center
Genomic Medicine Institute
Eng Lab – Translational Cancer Genetics/Genomics
Germline Predisposition and Cancer Risk Prediction
& Testing of
PTEN mutations/variations in CowdenPrioritization
syndrome (breast/thyroid)
SDH variants in Cowden syndrome Known High Penetrance
Cancer Genes in Setting of
KLLLN germline hypermethylation
Counseling
Nontraditional Mechanisms of PTENGenetic
Loss-of-Function
Nuclear-Cytoplasmic trafficking of PTEN
Multiple Generation
Pedigree
Epigenetic
modification
For Cancer Genetic Risk Assessment
FBE Gene Hunt
Clinical Screening,
Preventive Measures,
Behavior Modification
Multidisciplinary Cancer
Consult Including
Genomic Medicine
Complex
And Genetic Counseling
Select Multi-Agent Targeted
Disorders
Therapy With >99%
Germline
homozygosity & predisposition to common solid
tumors of Durable
Likelihood
Germline Variant Profiling
Response & <1% Likelihood
Of Adverse Effects
Biopsy of Cancer
Solid Tumor Microenvironment Genomics & Outcome
HNSCC Metabiomics
Histopathology
Somatic Genomic Profiling of
Cancer Epithelium & Stroma
Genomic Medicine Institute
Cowden Syndrome (CS) as a Model for Cancer Genetics Practice
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The Great Mimic
Difficult to Recognize
Under-Diagnosed
Autosomal Dominant
Multiple Hamartomas
High Risk of:
• Breast CA (50%)
• Thyroid CA, especially FTC (10%)
• International Cowden Consortium Diagnostic
Criteria
• Robust
• Complex
Genomic Medicine Institute
Key Features of CS are Difficult to Recognize
Papillomatous Papules
Trichilemmoma
(Pathognomonic Feature)
Genomic Medicine Institute
CS Component Neoplasias
• Established
– Breast Cancer (28-50%)
– Thyroid Cancer (10%)
– FTC
– Breast FBC/FA (75%)
– Thyroid Follicular
Hyperplasia or Adenoma
(67%)
– Lhermitte-Duclos Dz (x%)

Suspected





Endometrial CA
Renal Cell CA
Melanoma
Basal Cell CA
Glioneural Brain CA
Zbuk & Eng. Nature Rev Cancer 2007
Genomic Medicine Institute
Mapping of the CS Gene
• International Cowden Consortium Study
• 12 Extended CS Families
• 40 Affected Individuals
• CS Mapped to 10q22-q23
10p - short arm
10q - long arm
10q22-q23
Nelen et al. Nature Genet 1996
Genomic Medicine Institute
PTEN is the CS Gene
• 5 CS Families, Linkage to 10q22-q23
• Candidate Gene, PTEN, on 10q23.3
• Germline Mutations of PTEN, on 10q23.3, in 4 of
5 Families
– Family “without” mutation had highest LOD score on prior linkage
analysis (LOD>1)
Nelen et al. Nature Genet 1996
Liaw, Marsh et al. Nature Genet 1997
Genomic Medicine Institute
PTEN
• Phosphatase, Tensin-Homologue, Deleted on
Chromosome TEN
– 10q23.3
• Tumor Suppressor Gene
• Dual-Specificity Phosphatase
– Lipid & Protein Phosphatase
– Ser-Thr as well as Tyr Phosphatase
• Multiple Roles in Cell Cycle Arrest, Apoptosis,
Migration, Polarity, Genomic Stability, etc
Reviewed in Waite & Eng. AJHG 2003 & Zbuk & Eng. Nat Rev Cancer 2007
Genomic Medicine Institute
PTEN Hamartoma Tumor Syndrome (PHTS)
• Cowden syndrome (CS)
– PTEN Mutation Frequency - 85% (25% in new series)
• Bannayan-Riley-Ruvalcaba syndrome (BRRS)
– Mutation Frequency - 65%
– Rare, Autosomal Dominant Disorder: Macrocephaly, Lipomatosis,
Haemangiomatosis, Speckled Penis
• Proteus Syndrome (PS)
– Mutation Frequency - 20%
– Hemihypertrophy, etc (“Elephant Man”)
• Autism Spectrum Disorder (ASD) with Macrocephaly
– Mutation Frequency - 10-20%
Marsh et al. Nature Genet 1997
Zhou et al. Lancet 2001
Zbuk & Eng. Nature Rev Cancer 2007
Tan et al. Am J Hum Genet 2011
Genomic Medicine Institute
PHTS - What Are the True Associated Clinical
Neoplasias?
• Prospective Accrual
– Pilot Series: Jan, 1999-July 2005 (N=2205)
– Validation Series: Oct, 2005-Ongoing (N>3000)
• Eligibility: Relaxed from Classic CS Operational Dx
Criteria
• Clinical Feature Checklist
• Medical Records & Pathology Review
• Age at Diagnosis for Each Neoplasia
• PTEN Mutation Analysis, Including Promoter &
Large Deletion/Rearrangement Analyses
Tan et al. Am J Hum Genet 2011
Eng et al. Unpublished 2011
Genomic Medicine Institute
Over-Representation of Malignancies in PTEN Mutation
Positive Individuals
Increased
over Gen
Pop?
P-Value
(Chi-Square)
Breast (Female)
Yes
<0.001
Endometrium
Epith Thyroid
Yes
<0.001
Yes
<0.001
Eng et al. Unpublished 2011
Mester and Eng. ASHG 2009
Genomic Medicine Institute
PTEN Testing for Diagnosis
• (Pretty) Accurate Molecular Diagnostic Adjunct
– Must Include Intragenic PTEN (Exons 1-9), Promoter and Large
Deletion Analysis
• Helps with Cancer Risk Assessment and Management
• Predictive Testing is Possible
– Always Start with a Known Affected (Living)
– Family-Specific Mutation
– Test for Family-Specific Mutation in as Yet Unaffected First
Degree Relative(s)
Genomic Medicine Institute
Genetics-Enabled Molecular Diagnosis, Predictive
Testing & Medical Management
PTEN Testing, Affected Person, with Cancer Genetics Consultation
Mutn Negative
PTEN Mutn Positive
Promoter Analysis in CS
Deletion Analysis in BRRS
If Mutn Negative
If Mutn Positive
If Mutn Positive
To Research
STOP
Breast, Thyroid, Endometrial
Surveillance, Etc (NCCN)
If Mutn Negative
All First Degree Relatives of
Mutation Positive Individuals
Offered Gene Testing for
Family-Specific Mutation
Reviewed in Zbuk & Eng. Nature Rev Cancer 2007
Genomic Medicine Institute
What About Those Germline PTEN Mutation Negative
Patients?
• CS: 15% (75% - 2011) PTEN Mutation Negative
• CS-Like: 85% PTEN Mutation Negative
• BRRS: 35% PTEN Mutation Negative
• BRRS-Like: Who Knows?
• Proteus Syndrome: 80% PTEN Mutation Negative
• PS-Like: 40% PTEN Mutation Negative
Genomic Medicine Institute
Why is it Important to Find Genes and Mutations to
Account for a High Frequency of a Heritable Cancer?
Clinical Function
Known Gene and
Mutation(s)
Gene Unknown
Clinical Diagnosis
Yes
Yes if Clinically Classic
Molecular Diagnosis
Yes
No
Genetic Counseling
Yes
Yes but Cookie-Cutter
Gene-Informed Cancer
Risk Assessment
Yes
Can be Done but not
Gene-Informed
Predictive Testing
Yes
No
Gene-Informed
Management
Yes
No (Can Do CookieCutter Management)
Genomic Medicine Institute
Genes Encoding Succinate Dehydrogenase (SDH) as
Predisposition Genes in PTEN Mutation Negative
CS/CSL Individuals?
• Germline Heterozygous Mutations in SDHB, SDHC, SDHD
Cause Heritable Pheochromocytoma/Paraganglioma
(PC/PGL) Syndrome
• European-American PC-PGL Registry
• PC/PGL Individuals with SDHB Mutations
– 1-5% Had Renal Cell Carcinoma
– A Few Had Papillary Thyroid Carcinoma (PTC)
– Reminiscent of Component Neoplasias of CS
• Hypothesis: SDH Genes May be Novel Predisposition
Genes for PTEN Mutation Negative CS/CSL
Neumann et al. N Engl J Med 2002, JAMA 2004,
Vanharanta et al. Am J Hum Genet 2004, Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
Mitochondrial Complex II = SDH
Eng et al, Nat Rev Cancer 2003
Genomic Medicine Institute
SDHB-D Germline Mutation Analysis of PTEN Mutation
Negative CS/CSL Individuals
Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
MnSOD Expression Screen > SDHB-D Mutation Analysis
Increased ROS
Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
Variably Increased P-AKT and P-MAPK Resulting from
Germline PTEN Mutation Positive CS/CSL
Genomic Medicine Institute
Variably Increased P-AKT and P-MAPK Resulting from
Germline SDHB/SDHD Mutation/Variant Positive CS/CSL
Individuals without PTEN Mutations
Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
Proposed Cross-Talk Between PTEN and SDH Pathways
Genomic Medicine Institute
Cancer Risks in SDH Mutation/Variant Positive versus
Cancer Risks in PTEN Mutation Positive CS/CSL
Cancer
Renal
Thyroid
SDH Mut
2/10
5/10
Breast
6/9
Uterine
1/9
Colon
0/10
%
95% CI
PTEN Mut
20%
5-52%
50%
25-76%
66.7%
36-88%
11%
0-45%
0
0-32%
Ni et al. Am J Hum Genet 2008, Eng et al, unpublished
4/230
15/206
30/107
15/107
4/210
%
95% CI
1.2%
0.5-4.5%
7.2%
4-12%
28%
22-34%
14%
8-22%
6.7%
0.6-5%
P-Value*
0.03
<0.001
<0.001
0.64
>0.99
*Fisher 2-Tailed Exact Test
Genomic Medicine Institute
Proposed Clinical Algorithm for Gene Testing in CS
and CSL Probands
Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
Example of Work Flow for a Translational Genetics
Research (PTEN) Protocol & the Team Ensuring the Flow
PI Conceives of Hypotheses & Study Design & is Responsible for the Study Protocol.
PI can & does Delegate Various Responsibilities to Protocol Members
PI: C Eng; GC Coordinator: Jessi Mester; General Research Coordinator: Dawn Caraballo
CPGH Physicians and GC’s
CC/National/International Clinicians
Dawn, GC Assts, GCs
Gloria, Others Send Out Blood Kit
Dawn, Jessi x 2, GC Assts,
Student Interns, Others
Genomic Medicine Biorepository
Eng Lab Members
LabMatrix Entry: Kim and Tom
Genomics Core Facility
Mut+/Var+ Patients Choice of
Enrollment in Annual Questionnaire
Study
Mut + Results
Checked in CLIA
Lab -> to Patients
Gloria, GC Assts, Student Interns, Others
Dawn Offers Questionnaire Study;
A Whole New Protocol Rolls
CPGH Physicians and GC’s
CC/National/International Clinicians
Jessi Me (Mut+)
Dawn via email (Mut-)
Genomic Medicine Institute
Genetics-Enabled Cancer Risk-Assessment and Management: Paradigm
for Personalized Genetic Health Assessment and Management
Is it hereditary
or sporadic?
Cancer
Epidemiology says
10-15% caused by
High penetrance genes,
BUT which10-15%?
Personal & Family History
Age at Onset
Familial Clustering
One or More Organs
Pedigree Drawing
Low Risk
Standard Guidelines
General Population
High Risk
Pre-Test Genetic Counseling
Genetic Testing
Risk Management
Screening
Prophylactic Surgery
Test Positive
Receive Gene Test Results
Post-Test Counseling
Test Negative
Genomic Medicine Institute
Patients at Genetic Risk for Cancer Are Under-Served by
Not Being Systematically Recognized
• Cleveland Clinic Health System sees ~1.8 Million New
Patients/Yr
– 2009: 38 Million Total Visits
• ~10% of All with Disease Due to High Penetrance
Genetic Predisposition
• Should Have Referred >380,000 to Genetic Care in
2009
• In Reality, 2,900 were Referred in 2009
Eng et al., Unpublished
Genomic Medicine Institute
National Trends -- No Different
• >35,000 Healthy Patients
• ~350 Had Family Histories Consistent with Hereditary
Breast-Ovarian Cancer Syndrome Due to Germline
BRCA1/2 Mutations
• 35 of 350 Discussed Concerning Family History with
Any Healthcare Provider
• 4 of 35 Underwent BRCA1/2 Mutation Analysis
Levy D et al. 2009
Genomic Medicine Institute
Important Reasons that Individuals at Genetic Risk of
Disease are Under-Served
• Lack of systematic and comprehensive ascertainment of
individuals at genetic risk of disease;
• Traditional practice model for genetics in the context of
small workforce;
• Because of the exponential increase in genetics knowledge
in the last 10 years, there is a lag in knowledge acquisition
by both healthcare providers and the public.
– Fear of Genetic Discrimination (GINA passed in 2009)
• Genetics is a 21st century subspecialty on a 19th century
organizational structure
Genomic Medicine Institute
Potential Solutions that will Revolutionize GeneticsInformed Delivery of Healthcare
• To develop a process to ensure systematic and comprehensive
ascertainment of individuals at genetic risk of disease
– Beta Test with Cancer Genetics
• To increase access by changing the traditional practice model of genetics
– Beta Testing with Cancer Genetics (Very Successful)
– Same Day Service
– Quintupled Patient Volumes
• To engrain a multi-modality cancer genetics education campaign throughout
CCHS
– Point of Care Education
– Genetics Champions (Non-Genetics Healthcare Provider) in Each Institute
• Working with CC leadership to bring organizational structure and practice
models into the 21st century
– Integration of genetics into all of healthcare
– Standardization of practice
Genomic Medicine Institute
Who is Patient Population for Future Genomic Medicine?
Now
With Disease
Subclinical Disease(s)
Healthy
But: There are Only 500 Physicians who Practise Any Genetics, and There are
Perhaps 3000+/- Genetic Counselors in this Country!
Challenge to Researchers: Innovative Discoveries that Facilitate
Genetics-Informed Healthcare in Setting of Caregiver Shortage
Genomic Medicine Institute